Coarse‐grained models for studying protein diffusion along <scp>DNA</scp>

Bhattacherjee, Arnab; Krepel, Dana; Levy, Yaakov

doi:10.1002/wcms.1262

Cited by 27 publications

(31 citation statements)

References 99 publications

(114 reference statements)

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“…96 The present data should allow a similar approach to be used to derive potential functions for amino acid interactions with the bases, sugar and phosphate groups of DNA in both the single- and double-stranded states. CG simulation models have already been used in a number of very interesting studies of protein-DNA interactions; see, for example, the works of the Levy 97, 98 and Takada 99 groups, with at least one involving modeling of DNA in its single-stranded state. 100 The use of potential functions derived from atomistic simulations that have been shown to reproduce relative affinities of amino acids for dsDNA and ssDNA, could enable such simulations to achieve even higher levels of realism, especially in modeling processes such as DNA replication, in which both single- and double-stranded forms of DNA play important roles.…”

Section: Discussionmentioning

confidence: 99%

Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations

Andrews

Campbell

Elcock

2017

J. Chem. Theory Comput.

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Given the ubiquitous nature of protein-DNA interactions, it is important to understand the interaction thermodynamics of individual amino acid sidechains for DNA. One way to assess these preferences is to perform molecular dynamics (MD) simulations. Here we report MD simulations of twenty amino acid sidechain analogs interacting simultaneously with both a 70-base pair double-stranded DNA and with a 70-nucleotide single-stranded DNA. The relative preferences of the amino acid sidechains for dsDNA and ssDNA match well with values deduced from crystallographic analyses of protein-DNA complexes. The estimated apparent free energies of interaction for ssDNA, on the other hand, correlate well with previous simulation values reported for interactions with isolated nucleobases, and with experimental values reported for interactions with guanosine. Comparisons of the interactions with dsDNA and ssDNA indicate that, with the exception of the positively charged sidechains, all types of amino acid sidechain interact more favorably with ssDNA, with intercalation of aromatic and aliphatic sidechains being especially notable. Analysis of the data on a base-by-base basis indicates that positively charged sidechains, as well as sodium ions, preferentially bind to cytosine in ssDNA, and that negatively charged sidechains, and chloride ions, preferentially bind to guanine in ssDNA. These latter observations provide a novel explanation for the lower salt-dependence of DNA duplex stability in GC-rich sequences relative to AT-rich sequences.

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Section: Discussionmentioning

confidence: 99%

Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations

Andrews

Campbell

Elcock

2017

J. Chem. Theory Comput.

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“…The phenomenon of 1D diffusion of DNA-binding proteins on DNA has been observed using single-molecule experiments, [7][8][9][10][11] and analyzed by coarsegrained molecular simulations. [12][13][14][15][16][17][18] The theoretical framework describing facilitated diffusion on protein-DNA interactions is also well established. 6,[19][20][21] During 1D diffusion, the protein remains in contact with DNA by virtue of non-specific binding promoted by electrostatic interactions.…”

Section: Introductionmentioning

confidence: 99%

Roles of conformational disorder and downhill folding in modulating protein–DNA recognition

Chu

Muñoz

2017

Phys. Chem. Chem. Phys.

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Transcription factors are thought to efficiently search for their target DNA site via a combination of conventional 3D diffusion and 1D diffusion along the DNA molecule mediated by non-specific electrostatic interactions. This process requires the DNA-binding protein to quickly exchange between a search competent and a target recognition mode, but little is known as to how these two binding modes are encoded in the conformational properties of the protein. Here, we investigate this issue on the engrailed homeodomain (EngHD), a DNA-binding domain that folds ultrafast and exhibits a complex conformational behavior consistent with the downhill folding scenario. We explore the interplay between folding and DNA recognition using a coarse-grained computational model that allows us to manipulate the folding properties of the protein and monitor its non-specific and specific binding to DNA. We find that conformational disorder increases the search efficiency of EngHD by promoting a fast gliding search mode in addition to sliding. When gliding, EngHD remains loosely bound to DNA moving linearly along its length. A partially disordered EngHD also binds more dynamically to the target site, reducing the half-life of the specific complex via a spring-loaded mechanism. These findings apply to all conditions leading to partial disorder. However, we also find that at physiologically relevant temperatures EngHD is well folded and can only obtain the conformational flexibility required to accelerate 1D diffusion when it folds/unfolds within the downhill scenario (crossing a marginal free energy barrier). In addition, the conformational flexibility of native downhill EngHD enables its fast reconfiguration to lock into the specific binding site upon arrival, thereby affording finer control of the on- and off-rates of the specific complex. Our results provide key mechanistic insights into how DNA-binding domains optimize specific DNA recognition through the control of their conformational dynamics and folding mechanism.

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“…The model resolution is similar to a previously developed model (32,33) but varies significantly in terms of energetics. We adopted a coarse-grained representation of protein, where each amino acid is represented by a single bead placed at the respective Cα position (34). The energetics of the protein is described by a structure-based potential (35) (for details, see the Supporting text), which represents the funnel-like energy landscape for protein folding (35) and has been used extensively in studying protein-protein (36) and protein-nucleic acid interactions (37)(38)(39)(40)(41)(42)(43).…”

Section: Methodsmentioning

confidence: 99%

Mechanism of Dynamic Binding of Replication Protein A to ssDNA

Bhattarcharjee

Mondal

2020

Preprint

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Replication protein A (RPA) serves as hub protein inside eukaryotic cells, where it coordinates crucial DNA metabolic processes and activates the DNA-damage response system. A characteristic feature of its action is to associate with ssDNA intermediates before handing over them to downstream proteins. The length of ssDNA intermediates differs for different pathways. This means RPA must have mechanisms for selective processing of ssDNA intermediates based on their length, the knowledge of which is fundamental to elucidate when and how DNA repair and replication processes are symphonized. By employing extensive molecular simulations, we investigated the mechanism of binding of RPA to ssDNA of different lengths. We show that the binding involves dynamic equilibrium with a stable intermediate, the population of which increases with the length of ssDNA. The vital underlying factors are decoded through collective variable principal component analysis. It suggests a differently orchestrated set of interactions that define the action of RPA based on the sizes of ssDNA intermediates. We further estimated the association kinetics and probed the diffusion mechanism of RPA to ssDNA. RPA diffuses on short ssDNA through progressive 'bulge' formation. With long ssDNA, we observed a conformational change in ssDNA coupled with its binding to RPA in a cooperative fashion. Our analysis explains how the 'short-lived,' long ssDNA intermediates are processed quickly in vivo. The study thus reveals the molecular basis of several recent experimental observations related to RPA binding to ssDNA and provides novel insights into the RPA functioning in DNA repair and replication. Significance StatementDespite ssDNA be the common intermediate to all pathways involving RPA, how does the latter function differently in the DNA processing events such as DNA repair, replication, and recombination just based on the length of ssDNA intermediates remains unknown. The major hindrance is the difficulty in capturing the transient interactions between the molecules. Even attempts to crystallize RPA complexes with 32nt and 62nt ssDNA have yielded a resolved structure of only 25nt ssDNA wrapped with RPA. Here, we used a state-of-the-art coarse-grained protein-ssDNA model to unravel the detailed mechanism of binding of RPA to ssDNA. Our study illustrates the molecular origin of variations in RPA action during various DNA processing events depending on the length of ssDNA intermediates.

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Coarse‐grained models for studying protein diffusion along DNA

Cited by 27 publications

References 99 publications

Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations

Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations

Roles of conformational disorder and downhill folding in modulating protein–DNA recognition

Mechanism of Dynamic Binding of Replication Protein A to ssDNA

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